1. Treatment with the cystic fibrosis transmembrane conductance regulator (CFTR) protein corrector VX-659 in combination with tezacaftor–ivacaftor significantly improved measures of lung function and quality of life in cystic fibrosis (CF) patients with the Phe508del–Phe508del and Phe508del–minimal function (MF) genotypes compared to tezacaftor–ivacaftor and placebo, respectively.

2. During the two and four-week trial periods, no dose-limiting adverse events occurred from treatment with VX-659–tezacaftor–ivacaftor and the majority of side-effects were mild to moderate.

Evidence Rating Level: 1 (Excellent)

Study Rundown: While effective, the first-generation CFTR modulators are not curative for CF and do not produce sufficient clinical outcomes for CF patients with the Phe508del–MF genotype. VX-659 is a next-generation CFTR corrector developed to be complementary to the first-generation correctors (tezacaftor and lumacaftor) by working through a different mechanism. The present study established the in vitro efficacy of VX-659, and subsequently conducted phase 1 and 2 clinical trials to determine the safety and efficacy of VX-659 in combination with tezacaftor–ivacaftor in CF patients with both Phe508del–Phe508del and Phe508del–MF genotypes. The primary endpoints were safety and the absolute change in predicted forced expiratory volume in 1 second (FEV1) percentage. No dose-limiting adverse effects from triple combination therapy were found, and triple therapy demonstrated significant increases in the predicted FEV1 for both the Phe508del–Phe508del and Phe508del–MF genotype patients. The trial suggests triple-combination corrector-potentiator treatment is safe and effective for CF patients with either one or two Phe508del alleles. The publication came alongside a companion trial of another next-generation corrector, VX-445, which reported similar results.

This was a randomized, double-blind, placebo-controlled phase 2 trial that also included in vitro and phase 1 trial data. The study enrolled patients with both one and two Phe508del alleles, yielding data for approximately 90% of CF patients and for the Phe508del–MF subgroup that has no currently approved treatment. The trial was limited by the short duration and only provides proof of concept. Phase 3 trial data has yet to be reported.

In-Depth [randomized controlled trial]: The in vitro characteristics of VX-659 (alone and in dual and triple combination with tezacaftor–ivacaftor) were evaluated in human bronchial epithelial cells derived from CF patients with the Phe508del–Phe508del (n=3) or Phe508del–MF (n=4) genotype. Adult CF patients (n=12) with the Phe508del–MF genotype were then randomized to triple therapy with VX-659 (n=9) or placebo (n=3) to establish safety (phase 1 trial). The phase 2 trial consisted of three arms: 1) 63 Phe508del–MF patients randomized to one of three doses (80 mg, 240 mg, and 400 mg) of VX-659–tezacaftor–ivacaftor (n=53) or placebo (n=10), 2) 29 Phe508del–Phe508del patients randomized to VX-659–tezacaftor–ivacaftor (n=18) or placebo (n=11), and 3) 25 Phe508del–MF patients randomized to VX-659–tezacaftor–VX-561 (n=19; VX-561 is a deuterated form of ivacaftor that can be taken once daily) or placebo (n=6). The primary endpoints were safety, side-effect profile, and absolute change in the percentage of predicted FEV1 from baseline through day 29. Secondary endpoints included the absolute change in sweat chloride concentration and absolute change in Cystic Fibrosis Questionnaire–Revised (CFQ–R) respiratory domain score at day 29.

In vitro, VX-659–tezacaftor–ivacaftor increased functional chloride transport more than any individual compound or dual combination. The most common clinical side effects of VX-659–tezacaftor–ivacaftor were cough (25% of patients) and infective pulmonary exacerbation of CF (21%). No adverse events lead to interruption or discontinuation of the phase 1 trial, and the maximum severity of adverse effects was mild or moderate for the majority of patients in the phase 2 trial (53 of 57 patients, 93%). In the phase 2 trial, all doses of VX-659 significantly increased predicted FEV1 from baseline compared to placebo in patients with the Phe508del–MF genotype (P<0.001 for all doses). In Phe508del–MF patients treated with VX-659 at 400 mg in combination with tezacaftor–ivacaftor, the absolute change in FEV1 from baseline was 13.3 percent (95% confidence interval [CI], 9.5 to 17.1). The change in FEV1 in Phe508del–Phe508del patients compared to placebo was 9.7 (95% CI, 6.6 to 12.7; P<0.001). In the Phe508del–MF and Phe508del–Phe508del groups, VX-659 (400mg)–tezacaftor–ivacaftor decreased sweat chloride concentration -51.4 (95% CI, -57.8 to -44.9) and -42.2 (95% CI, -46.8 to -37.7) and increased the CFQ-R respiratory domain score 21.8 (95% CI, 13.6 to 30.0) and 19.5 (13.1 to 25.9) points, respectively. VX-561 demonstrated a similar safety and efficacy profile in triple combination therapy to that of VX-659.

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